PROJECT SUMMARY/ABSTRACT The burden of Alzheimer?s disease and related dementia is substantial and growing. We have no disease- modifying treatments for most dementia sub-types, including Alzheimer?s disease dementia, and recent Alzheimer?s disease treatment trials have been disappointing. Thus, identifying ways to prevent or delay Alzheimer?s disease and related dementia may be our best option for reducing disease burden. Ambient air pollution exposure is a promising target for interventions to prevent or delay Alzheimer?s disease and related dementia. While the existing evidence linking ambient air pollution exposures to cognitive health and dementia is suggestive, it is insufficient to justify action. In order to recommend or develop effective interventions to reduce dementia burden through reductions in ambient air pollution exposure, we must first establish whether specific pollutants impact cognitive health, either overall or in susceptible subgroups. Thus, we propose to estimate associations between ambient exposure to U.S. EPA-regulated criteria air pollutants (Aim 1) and components of particulate matter air pollution (Aim 2) with incident Alzheimer?s disease and related dementia and related outcomes, overall and in potentially susceptible subgroups (Aim 3). While we will consider multiple air pollutants, our grant focuses on testing hypotheses that higher midlife and cumulative, mid- to late-life exposures to fine particulate matter (PM2.5), ozone (O3), and specific metals (Cd, V, Mn, Ni, V, Cr, and Pb) are associated with incident dementia and related outcomes. To complete these aims, we will use data from the Atherosclerosis Risk in Communities (ARIC) study, a unique cohort with incredible longitudinal data collected from midlife to late life. We will estimate exposure to air pollutants at each participant?s residential address throughout 25 years of follow-up, from midlife to late life, using an ensemble/data-fusing approach combining two chemical transport models (CMAQ, UCD/CTI), two emission inventories (NEI and EDGAR), available monitor data, and a local dispersion model, to maximize prediction accuracy. We will then evaluate whether midlife exposures or cumulative exposures from midlife to late life impact (i) cognitive decline from midlife to late life (n=14,040), (ii) incident dementia systematically assessed according to research criteria during follow- up (n=14,040), or (iii) neuroimaging evidence of dementia-related pathology in late life in a representative subset of ARIC participants (n=1,841). We will also conduct extensive sensitivity analyses to address residual confounding, selection bias, and measurement error/uncertainty due to use of estimated exposures. Throughout we will leverage an External Advisory Panel to ensure the best possible science and lay the groundwork for future collaboration. In order to recommend or develop effective interventions to reduce dementia burden through reductions in ambient air pollution exposure, we must first determine whether there is a link between specific pollutants and Alzheimer?s disease and related dementia, as well as what groups are most affected. The proposed work will provide evidence needed to answer to these questions.